Can you remember what you were doing 25 years ago? Perhaps you were sending texts on a Nokia 3310, watching Friends episodes for the first – not hundredth – time, choosing the latest DVD to rent at Blockbuster or listening to music on a CD player.

Back in 2000, Google was a fledgling search engine, social media hadn’t been imagined and the smartphone revolution was years away. The Lily Foundation didn’t exist, and Liz was working at in a secondary school in Surrey, unaware of the journey that lay ahead.

While the world was adapting to a new millennium, researchers working on mitochondrial disease were embarking on a journey of discovery that would transform our understanding of this complex condition. 25 years later, the progress in mito research is just as remarkable as the technological advances we’ve seen in everyday life.

How far we’ve come in a quarter century

25 years ago, the treatment landscape for mitochondrial disease looked very different.

There were few clinical trials, limited understanding of how best to test potential treatments and many of the therapies being explored took a broad approach to supporting mitochondrial function. Today, researchers are investigating everything from targeted medicines to nucleoside and gene therapies, and some treatments for specific mitochondrial diseases have even begun to reach patients.

That change also spans almost the entire history of The Lily Foundation. When Liz founded the charity almost 20 years ago, there was far less research into mitochondrial disease, far less understanding of the individual conditions themselves and very few disease-specific treatment options for families.

A new international review, led by Dr Amel Karaa of Harvard Medical School in Boston, and co-authored by an international team including Dr Maria O’Hanlon, former Research Manager at The Lily Foundation, has traced that journey from 2000 to 2025.

The idea for the review came from the Mito Foundation in Australia and grew into an international collaboration involving researchers and patient organisations including Mito Canada, the POLG Foundation, United Mitochondrial Disease Foundation and The Lily Foundation. Recently published in Therapeutic Advances in Rare Disease, the review looked at more than 1,600 scientific and regulatory records and identified 71 clinical trials involving people with primary mitochondrial disease across 25 countries.

Why is developing treatments so challenging?

Mitochondrial disease isn't just one condition – it’s an umbrella term for a large group of genetic disorders that can affect people in very different ways. Even people with the same genetic change can have different symptoms, develop them at different ages and experience very different rates of progression, which makes testing potential treatments particularly complicated.

Earlier trials sometimes included people with a wide range of genetic diagnoses and symptoms, making it harder to see whether a treatment was helping a particular group. Researchers have also had to work out the best ways to measure change, because things such as walking distance and fatigue, while important to people living with a mitochondrial disease, can naturally vary and may not always give a complete picture of someone's condition.

These experiences have helped shape the way trials are designed today, with studies increasingly focused on more clearly defined groups of patients and measures that are better matched to the treatment being tested.

Treatments are becoming more targeted

The treatments themselves are changing too. Much of the earlier research looked at medicines such as antioxidants or metabolic therapies, which aimed to support how mitochondria function more generally. As our understanding of the genetic causes of mitochondrial disease has grown, researchers have increasingly been able to develop treatments aimed at particular genetic faults or biological processes.

The review found 14 gene therapy trials, most involving Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease that causes loss of vision. Nucleoside therapies are another developing area, providing cells with some of the building blocks they need to make and maintain mitochondrial DNA.

Some of this research has now led to approved treatments. Idebenone has been approved in Europe to treat LHON for several years, while treatments for Barth syndrome and thymidine kinase 2 deficiency (TK2d) were approved in the United States in 2025. The TK2d treatment has also been approved by the European Medicines Agency, although it’s not yet approved in the UK.

These approvals are an important sign of progress and, while they may only apply to certain mitochondrial diseases, they demonstrate that it’s possible for targeted treatments to make it through development and reach patients.

Learning how to run better trials

Finding a promising treatment is only part of the challenge, because researchers also need a reliable way to find out whether it works. For some mitochondrial diseases, there may only be a few hundred people affected worldwide, often of different ages, with different symptoms and living in different countries. Recruiting the large numbers of participants associated with a traditional clinical trial may simply not be possible.

This is one reason why natural history studies are so important. By following people with a condition over time, researchers can understand how it usually changes and build a picture of what might be expected without a new treatment. This can make it easier to recognise when a therapy is genuinely making a difference.

Researchers are also looking for better ways to measure that difference, including biological markers, or ‘biomarkers’, alongside measures of people's symptoms, daily function and quality of life. At the same time, more flexible approaches to clinical trials are being explored so that researchers can work with very small patient populations while still collecting the evidence needed to understand whether a treatment is safe and effective.

Making sure we measure what matters

The last 25 years have seen one of the biggest changes in the research landscape, and that’s the increasing involvement patients and families are having in the development of treatments. This change reflects a growing understanding that something which is straightforward to measure in a clinic isn't necessarily the thing that makes the biggest difference to someone's life.

Being able to walk a little further may matter, but so might having enough energy to get through a school or working day, being able to do more independently or experiencing less pain. Patients and families can help researchers understand which changes would be genuinely meaningful, as well as whether the demands of taking part in a trial are realistic.

The review makes the case for involving patients and patient organisations throughout treatment development, from deciding what a trial should measure and reviewing how it will work, through to sharing results and helping to make successful treatments accessible.

What have 25 years taught us?

Looking back, the distance between 2000 and today can seem astonishing. We’ve moved from dial-up internet to AI, from DVDs to streaming and from simple calls and text messages to complex smartphones that perform hundreds of tasks.

In mitochondrial disease research, the journey has been equally significant. Researchers know far more about mitochondrial disease, how potential treatments should be tested and why some previous approaches haven't worked, while many of the treatments now being investigated are more closely matched to specific conditions.

Effective treatments are still urgently needed for most forms of mitochondrial disease, and many of the approaches being studied today remain at an early stage. Even so, the authors describe the current landscape as one of ‘cautious optimism’ – there are no guarantees, but there are good reasons to be encouraged by the progress being made.

Today, we have more clinical trials, more targeted approaches and, for a small number of conditions, treatments that have made it all the way from research to approval. At the same time, researchers have a much better understanding of how to design trials, what needs to be measured and how patients and families can help shape research.

For families affected by mitochondrial disease, progress can never come quickly enough, but the field is in a very different place to 25 years ago. The science is stronger, the way potential treatments are tested is improving and there are more possibilities opening up for the future.

Find out more by reading the full paper: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future, in Therapeutic Advances in Rare Disease.